NAM is the official provider of online scientific reporting for the
8th International AIDS Society Conference on HIV Pathogenesis, Treatment
and Prevention (IAS 2015), which will take place in Vancouver, Canada,
19th-22nd July 2015.

Gilead Science's
recently approved hepatitis C virus (HCV) nucleotide polymerase inhibitor
sofosbuvir has demonstrated good efficacy in combination with ribavirin against
HCV genotype 2. Sofosbuvir plus ledipasvir, Gilead's first-generation NS5A
replication complex inhibitor, cures most hepatitis C genotype 1 with a treatment duration as short as 8 weeks.
Sofosbuvir/ledipasvir without ribavirin is not as effective against HCV genotype 3, however, and some data indicate it is
susceptible to viral resistance.

As part of its ongoing
hepatitis C drug development programme, Gilead is also testing a
next-generation NS5A inhibitor, GS-5816, which demonstrated potent activity
against HCV genotypes 1 through 6 in early studies. The company is developing a
co-formulation of sofosbuvir and GS-5816, similar to the sofosbuvir and
ledipasvir co-formulation it has already submitted for regulatory approval in Europe
and the US.

Gregory Everson of the University of
Colorado at Denver presented findings from a phase 2 clinical trial looking at
the safety and efficacy of sofosbuvir plus GS-5816 taken without ribavirin for
12 weeks in treatment-naive people with genotype 1-6 chronic hepatitis C.

This study included 154 previously
untreated hepatitis C patients without liver cirrhosis. About 60% were men,
most were white and the mean age was approximately 50 years. Nearly 30% had HCV
subtype 1a, which is considered most difficult to treat. In addition, 7% had
HCV subtype 1b, 14% had genotype 2, 35% had genotype 3, 9% had genotype 4, a
single individual had genotype 5 and 6% had genotype 6. About one-third had the
favourable IL28B CC gene variant associated with interferon responsiveness.

Participants in this open-label study were
randomly assigned to receive 400mg once-daily sofosbuvir plus either 25mg or
100mg once-daily GS-5816 for 12 weeks. They were followed after finishing
therapy to determine sustained virological response, or continued undetectable
HCV viral load at 12 weeks post-treatment
(SVR12), which is considered a cure.

SVR12 rates for people with genotype 1 were
96% using the 25mg GS-5816 dose and 100% using the 100mg dose. For people with
genotype 2, the corresponding rates were 91% and 100%, respectively, while the
cure rates for genotype 3 were 93% in both dose arms.

Turning to the less common genotypes – where
the numbers were too small to draw meaningful conclusions – genotype 4 SVR12
rates were 100% and 86%, respectively, in the 25mg and 100mg dose groups. The
single genotype 5 patient and all genotype 6 patients in both dose arms were
cured. Across all genotypes, overall SVR12 rates were 95% using the 25mg dose
and 96% using the 100mg dose.

Looking at the patients who did not
achieve SVR12, three people relapsed after completing treatment: one person
with genotype 1 taking 25mg GS-5816, one person with genotype 3 taking 25mg and
one person with genotype 3 taking 100mg. In addition, one person with genotype
3 was a non-responder during treatment, one person with genotype 2 died during
follow-up and one person with genotype 3 was found to be re-infected.

Genetic sequencing revealed that about
one-quarter of people with genotype 1-3 had pre-existing resistance-associated NS5A
viral variants. Among them, virological failure was more likely using the lower
GS-5816 dose (5% vs 2%). However, most people with pre-existing variants were
cured.

Treatment with sofosbuvir and GS-5816 was
generally safe and well-tolerated. Four people had serious adverse events,
three of them in the 25mg dose arms. However, no one discontinued for this
reason. The most common side-effects reported by at least 10% of participants were
fatigue, headache, nausea and constipation. No one developed anaemia, a
side-effect often seen with ribavirin.

"Sofosbuvir + GS-5816 for 12 weeks
resulted in SVR12 rates >90% in all HCV genotypes (1-6)," the
researchers concluded. "The presence of pre-treatment NS5A variants was
not predictive of failure to achieve SVR12”.

Everson noted
that a combination of sofosbuvir and GS-5816 is now being tested in two
harder-to-treat groups, previously treated hepatitis C patients and people with
cirrhosis.

Reference

Everson G et al. Safety
and efficacy of treatment with the interferon-free, ribavirin-free combination
of sofosbuvir + GS-5816 for 12 weeks in treatment naive patients with genotype
1-6 HCV infection. 49th Annual
Meeting of the European Association for the Study of the Liver (EASL), abstract
O111, London, 2014.

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